The epithelial Na+ channel / degenerin superfamily of ion channels comprises Na+ channels involved in various cell functions in Metazoa. Its members include the degenerins involved in touch sensitivity in C. elegans,, Pickpocket and related channels in D. melanogaster, the peptide-gated FANaC ion channels of the nervous system of mollusks, as well as the Epithelial Na+ channel (ENaC) and proton-activated acid-sensing ion channels (ASICs) which are both found in mammals. ENaC mediates Na+ transport in epithelia and is essential for sodium homeostasis (1). ASICs are present in the central and peripheral nervous system where they have different physiological and pathological functions, as the expression of fear, the sensation of pain and neurodegeneration after ischemia (2). All ENaC/degenerin family members are Na+-selective or -preferring ion channels with relatively low unitary conductance, and many have been shown to be inhibited by the diuretic amiloride. Biochemical and functional studies indicated that ENaC/degenerin channels are multimeric proteins whose subunits have two transmembrane domains, short intracellular N- and C-termini and a large extracellular part. The recently published crystal structure of ASIC1 showed a trimeric channel of the proposed subunit organization. Degenerins have been shown to form the channel part of a mechanotransduction complex in C. elegans, touch neurons. In analogy, a possible mechanosensitivity of ASICs and ENaC has been investigated. To date there is much evidence supporting an involvement of ASICs in mechanosensation, however the exact role of ASICs in mechanosensation is unclear. ENaC is a constitutively active channel, whose contribution to Na+ transport is regulated on the level of the expression of the protein, as well as by many modulators of channel activity, as for example proteases and Na+ ions. For ASICs, the only identified direct activators so far are protons. The ASICs are therefore considered as ligand-gated channels. We have recently applied a systematic approach to identify potential pH-sensing residues in ASIC1a. We calculated the pKa of all extracellular His, Glu and Asp residues using a Poisson-Boltzmann continuum approach based on the ASIC 3D structure, to identify candidate pH-sensing residues. The role of these residues was then assessed by site-directed mutagenesis and functional analysis (3). The localization of putative pH-sensing residues suggests that pH changes control ASIC gating by protonation / deprotonation of many residues per subunit in different channel domains, thus that protons act differently from larger ligands which bind to a low number of distinct binding sites. In conclusion, members of ENaC/degenerin subfamilies share a similar structural organization; however they differ in their activators and physiological roles. It is likely that parts of the gating machinery are common between different subfamily members.